AA metabolites derived via lipoxygenase (LO) mainly 12(S)-hydroxyeicosatetraenoic acid (HETE) and cytochrome P450 (CYP450) (20-HETE), pathways, cause vasoconstriction, vascular smooth muscle cell (VSMC) hyperplasia and/or hypertrophy. However, the mechanism by which these AA metabolites promote vascular remodeling during injury is not well understood. Our preliminary observations that a) spleen tyrosine kinase (p72Syk), a non-receptor tyrosine kinase, is also expressed in rat VSMC and it is activated by AA and its metabolites 5(S)-, 12(S)-, 15(S) and 20-HETE and also Ang II (which causes release of AA);b) inhibitors of p38 mitogen activated protein kinase (MAPK) and PKCzeta minimize Ang II-induced p72 Syk activation;c) AA and HETEs, like Ang II, promote neointima formation in balloon injured rat carotid artery;and d) Ang I induced neointima formation in the injured artery is attenuated by dominant negative p72 Syk have led us to the following central hypothesis: AA and its metabolites, mainly HETEs, promote neointima formation and stenosis by activating p72 Syk via activation of p38 MAPK and PKCzeta through the epidermal growth factor receptor (EGFR). To test this hypothesis, the following specific aims will be considered: Aim 1. To determine the expression and activation of p72 Syk by AA and its metabolite and Ang II in VSMC. Aim 2. To examine the relationship between AA and its metabolites and ERK1/2, p38MAPK, JNK, PKCzeta, EGFR and p72 Syk in VSMC. Aim. 3. To investigate the contribution of p72 Syk to neointima formation by AA and its metabolites (HETEs) and of Ang II to in vivo in balloon injured rat carotid artery. Aim 4. To determine the contribution of p72 Syk in vitro to VSMC-migration, proliferation, hypertrophy and extracellular matrix production in response to AA, HETEs, and Ang II. The proposed studies should advance our knowledge of the mechanism involved in vascular remodeling during injury and provide a rational approach for the development of novel agents for the treatment vascular diseases including restenosis and atherosclerosis.